title: Replacement of Thr32 and Gln34 in the C-terminal neuropeptide Y fragment 25-36 by cis-cyclobutane and cis-cyclopentane β-amino acids shifts selectivity toward the Y(4) receptor.
abstract: Neuropeptide Y (NPY) and pancreatic polypeptide (PP) control central and peripheral processes by activating the G protein coupled receptors YxR (x = 1, 2, 4, 5). We present analogs of the C-terminal fragments 25-36 and 32-36 of NPY and PP containing (1R,2S)-cyclobutane (βCbu) or (1R,2S)-cyclopentane (βCpe) β-amino acids, which display exclusively Y4R affinity. In particular, [βCpe(34)]-NPY-(25-36) is a Y4R selective partial agonist (EC50 41 ± 6 nM, Emax 71%) that binds Y4R with a Ki of 10 ± 2 nM and a selectivity >100-fold relative to Y1R and Y2R and >50-fold relative to Y5R. Comparably, [Y(32), βCpe(34)]-NPY(PP)-(32-36) selectively binds and activates Y4R (EC50 94 ± 21 nM, Emax 73%). The NMR structure of [βCpe(34)]-NPY-(25-36) in dodecylphosphatidylcholine micelles shows a short helix at residues 27-32, while the C-terminal segment R(33)βCpe(34)R(35)Y(36) is extended. The biological properties of the βCbu- or βCpe-containing NPY and PP C-terminal fragments encourage the future application of these β-amino acids in the synthesis of selective Y4R ligands.
authors.affiliation: Institute of Organic Chemistry, University of Regensburg , Universitätsstrasse 31, 93053 Regensburg, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Berlicki
authors.forename: Melanie
authors.initials: M
authors.lastname: Kaske
authors.forename: Raquel
authors.initials: R
authors.lastname: Gutiérrez-Abad
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Ona
authors.initials: O
authors.lastname: Illa
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Ortuño
authors.forename: Chiara
authors.initials: C
authors.lastname: Cabrele
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Oliver
authors.initials: O
authors.lastname: Reiser
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D003503:Cyclobutanes / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009478:Neuropeptide Y / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017476:Receptors, Neuropeptide Y / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D003503:Cyclobutanes; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C109491:neuropeptide Y4 receptor